Heart failure (HF) is a chronic and progressive disease associated with significant morbidity and mortality. As baroreflex dysfunction and neurohumoral activation contribute to the progression and poor prognosis associated with HF, therapies that favorably influence these factors are important to identify. The long-term goal of the PI is to better understand mechanisms underlying autonomic and cardiovascular abnormalities in HF. The short-term goal of the PI is to determine the effect omega-3 fatty acid supplementation exerts on baroreflex control of the circulation and neurohumoral activation in HF patients. The general working hypothesis being tested is that baroreflex dysfunction may contribute to neurohumoral activation in HF and that these factors may be favorably modified by omega-3 fatty acid supplementation. To address this topic studies with the following Specific Aims will be performed. To determine the effect of omega-3 fatty acid supplementation on: 1) muscle sympathetic nerve activity (MSNA) at rest and in response to baroreceptor loading/unloading in HF patients, 2) renal vasoconstrictor responses to baroreflex unloading in HF patients, and 3) neurohumoral activation and limb blood flow at rest and during baroreflex unloading in HF patients. Methods used to address these aims will include direct measures of efferent sympathetic nervous system outflow using peroneal microneurography, Doppler ultrasound estimates of renal blood flow velocity and whole limb blood flow, [central venous pressure], and numerous biochemical measures to assess the state of neurohumoral activation. In addition to obtaining measures at rest responses to changes in baroreceptor input (i.e., drug-induced changes in blood pressure and responses to graded central hypovolemic stress) will also be determined. These responses are important to study as baroreflex dysfunction in HF patients may underlie neurohumoral activation at rest as well as impaired modulation during application of physiological stress. Measurements obtained at study entry (baseline) will be repeated at weeks 6 and 12 of the intervention (omega-3 fatty acid supplementation) to gain insight into the temporal pattern of response. It is expected that neurohumoral activation and vascular resistance at rest will be reduced and abnormalities in baroreflex control of the circulation including modulation of neurohumoral activation will be, at least, partially restored by 12 weeks of omega-3 fatty acids supplementation in HF patients. Other groups studied will include HF patients receiving placebo (corn oil) as well as 2 groups of age-, BMI-, and gender-matched healthy adults receiving omega-3 fatty acid supplements (healthy experimental) or corn oil supplements (healthy control). Collectively, inclusion of these distinct groups will allow baseline differences attributable to HF, as well as the specificity of the responses to omega-3 fatty acids, to be determined. The findings from these novel studies will provide important insight into the therapeutic potential of omega-3 fatty acids in the management of human HF. PUBLIC HEALTH RELEVANCE: Despite significant advancements in our ability to treat heart failure with pharmacological substances this chronic and progressive disease still is associated with excessive rates of morbidity and mortality. Omega-3 fatty acids ('fish oil') may beneficially affect several important markers (neurohumoral activation and baroreflex function) associated with poor prognosis in heart failure patients. The novel studies outlined in this application will provide unique insight into the therapeutic potential of omega-3 fatty acid supplementation in the management of patients with heart failure.